Rosiglitazone is effective and well-tolerated in a range of therapeutic regimens during daily practice in patients with type 2 diabetes.

Subjects (N = 22,808) with inadequately controlled type 2 diabetes mellitus (T2DM) were included in a large 6-month observational study in Germany. Rosiglitazone (RSG) was added to existing therapy in line with daily practice, with 19,962 subjects evaluated for efficacy by treatment group: RSG monotherapy (n = 1017), RSG plus metformin (MET) (n = 7160), RSG plus sulphonylurea (n = 5033), triple oral therapy (n = 4247), and the remaining subject population (n = 2505). Overall, RSG significantly reduced median HbA(1c) and fasting blood glucose by 1.3% and 50 mg/dl over 6 months (p < 0.001 for both). The proportion of subjects achieving glycaemic goals of

Rosiglitazone plus metformin is effective and well tolerated in clinical practice: results from large observational studies in people with type 2 diabetes.

This study investigated the efficacy during daily practice of rosiglitazone (RSG) added to metformin (MET) in poorly controlled type 2 diabetes mellitus. Two post-marketing observational studies were conducted in Germany over 6 months. RSG (4 mg/day titrated to 8 mg/day as required) was added to existing MET in 11,014 subjects. Subjects were maintained on diet and exercise. Addition of RSG to MET significantly reduced median HbA 1c by 1.3% (8.1 vs. 6.8%; p < 0.0001) and median fasting blood glucose (FBG) by 47.0 mg/dl (171.0 vs. 124.0 mg/dl; p < 0.0001) after 6 months. The proportion of subjects achieving HbA(1c) targets of < or = 6.5 and < or = 7.0% increased from 3.5 to 38.8% and from 13.5 to 63.7%, respectively. Mean systolic and diastolic blood pressure decreased by 7 and 3 mmHg, respectively (p < 0.0001). Mean weight decreased by 1.7 kg and was constant or reduced in most (74.1%) subjects. Addition of RSG to MET significantly reduces median HbA 1c and FBG in clinical practice and is generally well tolerated.

Renal handling of human apolipoprotein(a) and its fragments in the rat.

The sites and mechanisms of the catabolism of atherogenic lipoprotein(a) (Lp(a)) are not well understood. Lp(a) is increased in patients with end-stage renal disease, suggesting a renal catabolism of Lp(a). To gain a better insight into renal handling of Lp(a), we established a heterologous rat model to study the renal catabolism of human Lp(a). Pure human Lp(a) was injected into Wistar rats, and animals were sacrificed at different time points (30 minutes to 24 hours). Intact Lp(a) was cleared from the circulation of injected rats with a half-life time of 14.5 hours. Strong intracellular immunostaining for apolipoprotein(a) (apo(a)) was observed in the cytoplasm of proximal tubular cells after 4, 8, and 24 hours. Apolipoprotein B (apoB) was colocalized with glomerular apo(a) 1 to 8 hours after Lp(a) injection, but renal capillaries and tubules remained negative. No relevant amounts of apo(a) fragments were found in the plasma of rats after injection of Lp(a). During all urine collection periods, apo(a) fragments with molecular weights of 50 to 160 kd were detected in the urine, however. Our results show that human Lp(a) injected into rats accumulates intracellularly in the rat kidney, and apo(a) fragments are excreted in the urine. The kidney apparently plays a major role in fragmentation of Lp(a). Despite the fact that rodents lack endogenous Lp(a), rats injected with human Lp(a) may provide a useful heterologous animal model to study the renal metabolism of Lp(a) further.

Quantification of lipoprotein(a) and apolipoprotein(a) in plasma and lipoprotein fractions in the hypertriglyceridemic state.

Lipoprotein(a) [Lp(a)] is a risk factor for coronary heart disease (CHD) in particular in association with high low density lipoprotein (LDL) cholesterol concentrations. Hypertriglyceridemia on the other hand has been found to be associated with low Lp(a) values. This observation could be confirmed in 851 patients of the outpatient lipid clinic. Lp(a) median levels were 2.7-fold higher in patients with triglycerides below 200 mg/dl as compared with patients expressing triglyceride levels above 200 mg/dl (19 vs 7 mg/dl, P < 0.0001). In contrast to these data apolipoprotein(a) [apo(a)] has been detected in triglyceride-rich lipoproteins (TRL). To find out whether the presence of apo(a) in TRL is determined by the concentration of these particles, apo(a) concentrations were measured in TRL in fasting plasma of ten hypertriglyceridemic patients and ten normal controls with Lp(a) serum levels above 25 mg/dl. The apo(a) concentration in TRL did not show statistically significant differences between controls and patients (2.0+/-0.9 vs 1.8+/-1.6 mg/dl). In the second part of the study apo(a) levels in TRL were measured before and after fat feeding in eight healthy volunteers. Again no significant differences were observed in the apo(a) concentrations of the d < 1.006 a ml fraction before and after fat feeding (1.03+/-1.06 vs 0.81+/-0.63 mg/dl). In summary, this study fails to show an association of apo(a) with TRL for different states of hypertriglyceridemia. This negative finding is shown for constant particle numbers but might not be true if the particle number in TRL increases.

Cellular uptake of lipoprotein[a] by mouse embryonic fibroblasts via the LDL receptor and the LDL receptor-related protein.

The sites and precise mechanisms of the catabolism of the atherogenic lipoprotein[a] (Lp[a]) are unknown. It has been proposed that the low density lipoprotein receptor (LDL-R) and the low density lipoprotein receptor-related protein (LRP) are involved in the catabolism of Lp[a]. To address the question whether and to what extent the LDL-R and/or LRP are involved in the catabolism of Lp[a], we studied the cellular uptake of Lp[a] via those two receptors using mouse embryonic fibroblast (MEF) cell lines lacking either the LDL-R, the LRP, or both receptors due to disruption of the respective mouse genes. 125I-labeled LDL and 125I-labeled Lp[a] uptake by wild-type fibroblasts (MEF1) was compared with that by fibroblasts homozygous for the disrupted LRP allele (MEF2), fibroblasts with two defective alleles for the LDL-R (MEF3), and fibroblasts homozygous for defects both in the LDL-R and LRP gene (MEF4). Compared with MEF1, 125I-labeled LDL uptake by MEF2 was 77%, by MEF3 30%, and by MEF4 24% of that by MEF1. However, no significant differences in the specific 125I-labeled Lp[a] uptake by the four mouse embryonic cell lines was observed. In comparison with MEF1, the 125I-labeled Lp[a] uptake by MEF2 was 98%, by MEF3 111%, and 73% by MEF4. Approximately 50% of the total cellular uptake of 125I-labeled Lp[a] was nonspecific. In conclusion, our results suggest that Lp[a] is a poor ligand for the LDL receptor and the LRP. The data of the displacement studies, however, indicated that the nonspecific uptake of Lp[a] constitutes a major route for the cellular Lp[a] catabolism in this study.

Differences in lipoprotein (a) and apolipoprotein (a) levels in men and women with advanced coronary atherosclerosis.

BACKGROUND: This study was designed to evaluate whether differences between sexes exist in serum-lipoprotein (a) [Lp(a)] and arterial-wall-apolipoprotein (a) [Apo(a)] levels in patients with advanced coronary artery disease. METHODS: The concentrations of Lp(a) in serum and Apo(a) in aortic biopsies were studied in 76 men and 20 women undergoing coronary artery bypass graft surgery. The severity of coronary artery disease was determined by a coronary atherosclerosis score that used quantitative coronary angiography. RESULTS: Serum-Lp(a) and tissue-Apo(a) do not correlate with the severity of coronary artery disease as expressed by the coronary atherosclerosis score (r = 0.09 and r = 0.14, respectively). Women were older (65 +/- 8 versus 57 +/- 8 years, P < 0.001) and had higher mean Lp(a) and higher mean Apo(a) levels (47 +/- 41 versus 32 +/- 40 mg/dl and 33 +/- 34 versus 19 +/- 24 micrograms/g wet weight, P < 0.05) than men with identical coronary atherosclerosis score (35 +/- 8 versus 33 +/- 8, P > 0.05). The serum levels of cholesterol, triglycerides, and high-density lipoprotein were similar in both groups. CONCLUSIONS: Men and women undergoing coronary artery bypass graft surgery had very similar severity of coronary artery disease as expressed by the coronary atherosclerosis score. Women were 8 years older and had 1.5 times higher mean serum-Lp(a) levels and 1.75 times higher mean tissue Apo(a) levels higher than the men. Sixty per cent of the women but only 39% of the men had serum Lp(a) levels higher than 25 mg/dl. Lp(a) level seems to be an additional risk factor for coronary artery disease confined to postmenopausal women.

Extraction of lipoprotein(a), apo B, and apo E from fresh human arterial wall and atherosclerotic plaques.

Several studies have analysed apo(a) quantitatively in arterial wall tissue derived from post mortem samples. The purpose of this study was a qualitative analysis of Lp(a) in fresh human arterial wall tissue. It was evaluated whether Lp(a) exists as an intact lipoprotein or whether it is degraded. Additionally it was analysed whether there are differences in the apolipoprotein composition between lesion-free and diseased human arterial wall tissue. Serum and intimal tissue samples taken from the abdominal aorta and the inferior caval vein of 18 organ donors were analysed for lipids, Lp(a), and apolipoproteins apo B and apo E. Serum and tissue parameters were correlated. In the aortic tissue, higher Lp(a) and apolipoprotein levels were observed in the diseased samples. The total amount of Lp(a) recovered during three different extraction procedures was 5 micrograms/g wet weight in tissue free of plaque and 11.8 micrograms/g wet weight in atherosclerotic tissue. The corresponding values for apo B and apo E were 4.3 and 6.1 micrograms/g wet weight vs. 5.0 and 9.1 micrograms/g wet weight. After density gradient centrifugation of the aortic tissue extracts, it was shown that the major parts of apo(a) and apo B detected in the lesion-free vessel wall were present as Lp(a)-like particles. In the diseased tissue Lp(a) was partly dissociated into LDL-like particles and free apo(a). With this study we confirm that Lp(a) accumulates in the arterial wall, preferentially in diseased tissue, and that Lp(a) particles, deposited in atherosclerotic plaques, are partly degraded to LDL-like particles and free apo(a) in atherosclerotic plaques.

[Association of lipoprotein (a) with the extent of coronary atherosclerosis in surgically revascularized men and women]. / Assoziation von Lipoprotein (a) mit dem Ausmass der koronaren Atherosklerose bei chirurgisch revaskularisierten Männern und Frauen.

Lipoprotein (a) (Lp(a)) levels are genetically determined and levels higher than 25 mg/dl are associated with increased prevalence of coronary artery disease (CAD). We studied gender differences in 76 men and 20 women undergoing coronary artery bypass graft surgery (CABG) for a potential association between Lp(a) levels both in serum and the aortic wall (Apo(a)) and the severity of CAD determined by an atherosclerosis score (CS) using quantitative coronary angiography (QCA). Serum Lp(a) and tissue Apo(a) do not correlate with the severity of CAD as assessed from QCA (r = 0.09 and r = 0.14, resp.). 60% of women but only 39% of men had serum Lp(a) levels higher than 25 mg/dl. Women were 8 years older (65 +/- 8 vs. 57 +/- 8 years, p < 0.001) and had 1.5 times higher mean serum Lp(a) and 1.75 times higher mean tissue Apo(a) levels (47 +/- 41 vs. 32 +/- 40 mg/dl and 33 +/- 34 vs. 19 +/- 24 micrograms/g WW, p < 0.05) than men with identical CS (35 +/- 8 vs. 33 +/- 8, p = NS). The serum levels of cholesterol, triglycerides, and high-density lipoprotein were similar in the two groups. There is no association between Lp(a) and Apo(a) and the severity of coronary atherosclerosis in men and women undergoing coronary artery bypass surgery.

Disseminated cryptococcosis in a patient with AIDS.

We report the case of a 31-year-old AIDS patient who had generalized cryptococcal disease with involvement of the lungs, bone marrow, gastrointestinal tract and skin as well as chorioretinitis which may have been due also to Cryptococcus neoformans infection. Initially there was no involvement of the central nervous system. The patient recovered after 43 days' treatment with fluconazole and amphotericin B and flucytosine initially. Four months later he presented with a cryptococcal splenic abscess despite secondary prevention with fluconazole and twice-weekly liposomal amphotericin B. After splenectomy the patient was discharged in good health. One year later he died of cryptococcal meningitis.

Correlation of apolipoprotein(a) isoproteins with Lp(a) density and distribution in fasting plasma.

Lp(a) is an LDL-like lipoprotein which contains an additional apolipoprotein called apo(a). Apo(a) exhibits a significant size polymorphism and its size is inversely correlated with plasma Lp(a) levels. We investigated the distribution of different apo(a) isoproteins in lipoprotein density fractions. Fasting plasma samples were subjected to non-equilibrium density gradient ultracentrifugation. After SDS-PAGE and anti-apo(a) immunoblotting, apo(a) concentrations in individual density fractions were evaluated by densitometry. In series I, analysis of selected density fractions from 35 coronary heart disease (CHD) patients demonstrated that although most of the apo(a) was present in the Lp(a) density range, apo(a) was consistently found in both the VLDL and IDL fractions as well. In series II, density fractions from 9 normolipidemic subjects with 6 different apo(a) isoproteins were evaluated. A strong association between the size of the apo(a) isoprotein and the density of the associated Lp(a) particle was established (r = 0.976, P less than 0.001). Lp(a) densities ranged from 1.057 g/ml for the B isoprotein to 1.09 g/ml for the S5 isoprotein. Overall, 75% of the total apo(a) was detected in the Lp(a) density range (d = 1.05-1.12 g/ml), with 9% and 10% in the LDL (d = 1.019-1.05 g/ml) and HDL (d = 1.12-1.21 g/ml) fractions, respectively. VLDL contained an average of 4% of the total apo(a) in fasting normolipidemic plasma. Two hypertriglyceridemic subjects had substantially greater amounts of apo(a) in the fasting triglyceride-rich fraction. The results of this study indicate that the size of the apo(a) isoprotein strongly influences the density of its associated Lp(a) particle and that apo(a) is consistently found in the triglyceride-rich lipoproteins of fasting plasma.

Lipoprotein(a) in the arterial wall.

We compared CHD patients with healthy blood donors to confirm the role of Lp(a) as an independent risk factor. More important, we performed biochemical and immunohistochemical studies to evaluate the potential mechanism by which Lp(a) causes CHD. We measured the Lp(a) concentration in comparison with other lipoprotein parameters in fresh human arterial wall biopsies and, in autopsy tissue, we localized apo (a) and apo B, as well as fibrin, with immunohistochemical methods in different vessel areas. Density gradient ultracentrifugation was used to analyse lipoprotein fractions isolated from human arterial wall. Lp(a) accumulates in the intima, preferentially in plaque areas, dependent on the serum Lp(a) level. Most of the Lp(a) can be located extracellularly, but apo(a) can also be detected in foam cells. A strong co-localization has been observed for apo(a) and apo B; only a few areas containing only apo B were detected. Moreover, a striking co-localization for apo(a) and fibrin was found. The possibilities for the pathways by which Lp(a) enters the arterial wall and accumulates extracellularly are discussed on the basis of the present data and recent data published by other groups.

Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients.

The aim of this study was to determine the extent of accumulation of lipoprotein(a) [Lp(a)] in human arterial wall and to define its potential role in atherogenesis. Biopsies routinely taken from the ascending aorta of 107 patients undergoing aortocoronary bypass surgery were analyzed for lipid and lipoprotein parameters, which were then correlated to serum values. A significant positive correlation was established between serum Lp(a) and arterial wall apolipoprotein (apo)(a) by enzyme-linked immunosorbent assay. High serum Lp(a) also led to a significant increase of apo B in the arterial wall. No significant correlation was found between apo B in serum and aortic tissue. Apo B was found to be partially linked to apo(a) in the aortic extract. Furthermore, apo(a) was found to be intact, as determined by its molecular weight in sodium dodecyl sulfate electrophoresis. This technique also revealed that the apo(a) isoform pattern of aortic homogenate was comparable to the individual serum pattern. Immunohistochemical methods demonstrated a striking colocalization of apo(a) and apo B in the arterial wall, predominantly located extracellularly. Both proteins were increased in atherosclerotic plaques. With density gradient ultracentrifugation, Lp(a)-like particles could be isolated from plaque tissue. This initial study showed that Lp(a) accumulates in the arterial wall, partly in the form of lipoprotein-like particles, therefore contributing to plaque formation and coronary heart disease.

Determination of splenic blood flow by inhalation of radioactive rare gases.

We have evaluated the 133Xenon inhalation method for the determination of splenic blood flow. In twenty-two healthy persons the blood flow was on average 109 +/- 4 mg/100 g X min, which is equivalent to a total blood flow of about 170 ml/min. In patients with chronic fatty liver hepatitis specific blood flow was reduced (81 +/- 10 ml/100 g X min) as it was in patients with cirrhotic liver without splenomegaly (75 +/- 2 ml/100 g X min). With increasing weight of the spleen, the total blood flow rises, although specific blood flow is low. Our results obtained by the 133Xenon inhalation method are similar to results obtained by others using intraarterial injection of tracer gas. The advantages of the inhalation method as a non-traumatic method are: (1) the stress for the patient is very small; (2) blood flow measurements can be repeated within short periods of time. We consider for the present the 133Xenon inhalation method to be the method of choice for the determination of the splenic blood flow.

Determination of the specific blood flow of the liver by inhalation of radioactive rare gases.

The technique applying the inhalation of radioactive rare gase is a new method to determine the specific blood flow of the liver. After inhalation of 133Xe, the course of activity is registered above liver and spleen as well as in the exspirated air. The perfusion is calculated from the resulting wash-out curves. The average value in healthy persons is 91 +/- 15 ml/100 g min. The reproducibility is 5 +/- 1%. The xenon wash-out is delayed in cirrhotic livers; the blood flow is significantly decreased and amounts to an average of 45 ml/100 g min. A delayed wash-out of xenon was also found in major fatty livers due to the high affinity of xenon to fat. The dependence of the partition coefficient on the fat content was investigated by Kitani and Winkler in homogenized liver tissue of different fat content. The question arises whether these in vitro findings can be transferred to in vivo wash-out curves. We therefore carried out first investigations on patients of known content of fat of the liver, applying a 85MKr-133 Xe-double measurement. According to results which have been achieved up to now, sufficient accuracy can only be obtained up to a fat content of 10%.